Hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in Western countries. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e., several grams at a time, and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents which function by limiting cholesterol biosynthesis via inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products, such as mevastatin, lovastatin and pravastatin, and semisynthetic analogs, such as simvastatin. These compounds have the following chemical structural formulae: ##STR2##
Recently, MEVACOR.RTM., which contains lovastatin as the active agent, was approved by the Food and Drug Administration for use as an antihypercholesterolemic drug.
Numerous analogs and homologs of these compounds have been described in the patent literature. U.S. Pat. No. 4,444,784 discloses analogs of lovastatin which possess polyhydronaphthyl moieties and various 8-acyloxy groups attached thereto. U.S. Pat. No. 4,661,483 also discloses analogs of lovastatin wherein the 8-acyloxy group has been elaborated. Additionally, co-pending U.S. applications Ser. Nos. 859,513, 859,524, 859,525, 859,530, 859,534, and 859,535 all filed on May 5, 1986, disclose further analogs of lovastatin which have functionalized 8-acyloxy groups. All Of the lovastatin analogs, including simvastatin, which contain a 6-methyl group have that substituent in the natural 6.alpha. (axial) configuration.
Co-pending U.S. patent application, Ser. No. 048,136 filed May 15, 1987, discloses compounds which are analogs of lovastatin and related compounds which possess a hydroxymethyl group, acyloxymethyl group, carbamoyloxymethyl group, a carboxy group, an alkoxycarbonyl group or a carbamoyl group substituted on the 6-position of the polyhydronaphthyl moiety. The compounds in this application may possess a substituent in the 6-position in either the 6.alpha. or 6.beta. stereochemical position.
Co-pending U.S. patent application, Ser. No. 092,354 filed Sept. 2, 1987, discloses compounds which are analogs of lovastatin and related compounds which possess a methyl group in the 6-position in the 6.beta. stereochemical position.
Co-pending U.S. patent application, Attorney Docket No. 17703, filed contemporaneously herewith, discloses compounds which are analogs of lovastatin and related compounds which contain gemdisubstitution at the 6,6 positions of the polyhydronaphthyl moiety.
Co-pending U.S. patent application, Attorney Docket No. 17706, filed contemporaneously herewith, discloses compounds which are analogs of lovastatin and related compounds which contain two double bonds in the 4,4a- and 5,6- positions or one double bond in the 5,6- position of the polyhydronaphthyl moiety.